megaloblastic anemia teoman soysal prof.md. megaloblastic anemia a subclass of macrocytic anemia a...
TRANSCRIPT
Megaloblastic Megaloblastic AnemiaAnemia
Teoman SOYSAL Prof.MDTeoman SOYSAL Prof.MD
Megaloblastic AnemiaMegaloblastic Anemia
A subclass of macrocytic anemia A subclass of macrocytic anemia
(under morphologic classification)(under morphologic classification)
OrOr A subclass of anemias due to A subclass of anemias due to
defective DNA synthesis defective DNA synthesis
(pathogenetic classification)(pathogenetic classification)
Megaloblastic AnemiaMegaloblastic Anemia
Main causes of “Megaloblastic Main causes of “Megaloblastic Anemia”Anemia”– Vit.B12 deficiencyVit.B12 deficiency– Folic acid deficiencyFolic acid deficiency– OthersOthers
Megaloblastic AnemiaMegaloblastic Anemia
30-50 % of all macrocytic 30-50 % of all macrocytic anemias are caused by folic acid anemias are caused by folic acid and/or Vit.B12 deficiency.and/or Vit.B12 deficiency.
Vit B12Vit B12
Metabolic active cobalamins in the Metabolic active cobalamins in the body are;body are;– Methyl cobalamin and adenosyl cobalaminMethyl cobalamin and adenosyl cobalamin
Hydroxocobalamin can be reversed to Hydroxocobalamin can be reversed to the above cobalamins.the above cobalamins.
Pharmacy:Pharmacy:– Most stable cobalamin: cyanocobalaminMost stable cobalamin: cyanocobalamin
Vit B12Vit B12
Natural formsNatural forms– Produced by microorganisms Produced by microorganisms
(bacteria/fungi)(bacteria/fungi)– Plants do not produce or contain Vit Plants do not produce or contain Vit
B12 (except contamination)B12 (except contamination)– Colonic bacterial production occurs Colonic bacterial production occurs
but their location is distal to the site but their location is distal to the site of absorbtionof absorbtion
Vit.B12Vit.B12
Food sources rich in Vit.B12Food sources rich in Vit.B12 – LiverLiver– KidneyKidney– MuscleMuscle– EggEgg– Milk ,Cheese and other diary Milk ,Cheese and other diary
productsproducts– SeafoodSeafood
Plants are not sources Plants are not sources of Vit.B12of Vit.B12
Vit.BVit.B1212
Daily requirementsDaily requirementsAgeAge Amount/dayAmount/day
0 - 1 0 - 1 0.3 – 0.5 0.3 – 0.5 g, g,
1 – 10 1 – 10 0.7 – 1.5 0.7 – 1.5 g g
AdultsAdults 22g .g .
Pregnancy Pregnancy (2 (2g + ) g + )
22ndnd Trimestr Trimestr 0.50.5gg
33rdrd TrimestrTrimestr 11g g
Lactation Lactation 2.5 – 3 2.5 – 3 gg
Vit.B12Vit.B12
Average diet contains Average diet contains 5 – 305 – 30 g Vit. Bg Vit. B1212 dailydaily
The amount of Vit. BThe amount of Vit. B12 12 in the body is about in the body is about 2 – 52 – 5 mg. mg.
Most of it is in the liver. Most of it is in the liver. The store is sufficient for The store is sufficient for 3-63-6 years in case years in case
of impaired absorbtion.of impaired absorbtion. The storage form is mainly The storage form is mainly
adenosylcobalamin. adenosylcobalamin.
stomach
Enterohepatic circulation
Ileum cells
Pancreas enzymes
Parietal cell
Duodenum and jejunum
B12 in diet R-Binder
R - B12
R- B12
B12 B12
IF B12
TC II
B12
İleum
IF
IF - B12
Vit.BVit.B1212
Circulates with TCII and TCI in plasma.Circulates with TCII and TCI in plasma. Generally in the form of methylcobalamin.Generally in the form of methylcobalamin. Although most of the B12 is bound to Although most of the B12 is bound to
TCI ,TCI , TCII is the functional carrier, rapidly TCII is the functional carrier, rapidly
cleared from plasma.cleared from plasma. TCII deficiency is a cause of megaloblastic TCII deficiency is a cause of megaloblastic
anemia.anemia.
Vit .BVit .B1212
Plazma level of Vit. BPlazma level of Vit. B1212
200 - 900 ng/ L200 - 900 ng/ L
Functions of Vit.BFunctions of Vit.B1212
1)1)
Methylmalonyl co - A mutaseMethylmalonyl co - A mutase
Methylmalonyl co - A succinyl co - AMethylmalonyl co - A succinyl co - A
5-deoxyadenosyl 5-deoxyadenosyl BB1212
Functions of Vit.BFunctions of Vit.B1212
2- 2-
Methyl FHMethyl FH44 FHFH44
HomocysteinHomocystein MethioninMethionin
SAMSAM
BB1122
Methionin synthase
Folic AcidFolic Acid
Pteroyl glutamic acid and similar compounds arePteroyl glutamic acid and similar compounds are
termed as folic acid .termed as folic acid .
Polyglutamate is the Polyglutamate is the natural form.natural form.
Dihydro or tetrahydro folate are Dihydro or tetrahydro folate are metabolic active formsmetabolic active forms..
Folic acidFolic acid
Sources :Sources : Produced by plants and some Produced by plants and some
microorganismsmicroorganisms Folate rich foods;Folate rich foods;
– vegetables (Green leaf), vegetables (Green leaf), – Liver and kidney (parenchymal organs)Liver and kidney (parenchymal organs)
– Molds.Molds.
Folic acidFolic acidDaily requirementsDaily requirements
AgeAge
0 - 10 0 - 10 3.63.6g /kg g /kg > 10 > 10 33g /kgg /kg Pregnants Pregnants 500 500 g g Lactation +100 Lactation +100 g g
Diet contains 100 - 500 Diet contains 100 - 500 g folate/dayg folate/day..
Folate absorbtionFolate absorbtion
Mainly jejunum. Mainly jejunum.
In the form of monoglutamate . In the form of monoglutamate .
Methyltetrahydrofolate monoglutamate Methyltetrahydrofolate monoglutamate is is
the form it is found in serumthe form it is found in serum . .
Folate levels:Folate levels:
Normal rangesNormal ranges Serum:Serum: 6 – 21 6 – 21 g/L g/L (RBC volume) (RBC volume)
Red cell: Red cell: 160 – 640 160 – 640 g/L g/L (RBC volume)(RBC volume)
Folate deficiencyFolate deficiency Serum folate : Serum folate : <4<4g /L g /L Red cell folate: Red cell folate: <140<140g /Lg /L
Folate storesFolate stores
Total body folate:Total body folate: 5 – 20 mg 5 – 20 mg
Storage place :Storage place : LiverLiver
Storage form: Storage form: Methyl-Methyl-FHFH44
polyglutamatepolyglutamate
Functions of folic acid:Functions of folic acid:
Transfer of methyl or formyl groups to otherTransfer of methyl or formyl groups to other compounds. compounds. egeg-During the production of thymidylate for the synthesis of -During the production of thymidylate for the synthesis of
DNA (methylation of deoxyuridylate)DNA (methylation of deoxyuridylate)Source of the 1-carbon moieties;Source of the 1-carbon moieties;1-serine1-serineSerine + THF glycine + N-methylene THFSerine + THF glycine + N-methylene THF
2-Formiminoglutamic acid2-Formiminoglutamic acidFormiminoglutamate+FH4 glutamate+N-formimino THFFormiminoglutamate+FH4 glutamate+N-formimino THF
Dihydrofolate
THFA
Methylene
THFA
Deoxyuridilate Thymidilate DNA-thymine
Methyl THFA
Homocystein
Methyonine
B12
Dihydrofolate reductaseserin
e
glycine
Thymidylate synthase
Megaloblastic HematopoiesisMegaloblastic Hematopoiesis
Anemia +/- leukopenia +/- Anemia +/- leukopenia +/- thrombocytopenia.thrombocytopenia.
Causes of cytopeniasCauses of cytopenias : :
1-DNA synthesis is deranged 1-DNA synthesis is deranged
2-Ineffective hematopoiesis2-Ineffective hematopoiesis
3-Shortened RBC survival3-Shortened RBC survival
Causes of Causes of Megaloblastic AnemiaMegaloblastic Anemia Vit. BVit. B1212 deficiency deficiency Folate deficiencyFolate deficiency Other causesOther causes
Causes of VitBCauses of VitB12 12 deficiencydeficiencyI-Decreased intakeI-Decreased intake
( complete vegetarianism)( complete vegetarianism)
II-Impaired absorbtionII-Impaired absorbtion Gastric causes Gastric causes
( ( Pernicious anemiaPernicious anemia, gastrectomy , caustic injury, Zollinger-Ellison ), gastrectomy , caustic injury, Zollinger-Ellison ) Intestinal causesIntestinal causes
( Ileal resection or disease,eg:sprue,blind loop syndr,Diph.Latum, )( Ileal resection or disease,eg:sprue,blind loop syndr,Diph.Latum, )
Pancreatic disease-(insufficiency) Pancreatic disease-(insufficiency) Familial selective Vit BFamilial selective Vit B1212 absorbtion defect (Imerslund –Grasbeck) absorbtion defect (Imerslund –Grasbeck) DrugsDrugs( PAS, colchicin, neomycine, omeprazol,potasyum chloride,ethanol )( PAS, colchicin, neomycine, omeprazol,potasyum chloride,ethanol )
III-III-Other causesOther causes
Causes of folate Causes of folate deficiencydeficiency
Decreased intakeDecreased intake Increased demandsIncreased demands Drug related folate insufficiencyDrug related folate insufficiency
Causes of Folate Causes of Folate deficiencydeficiency
A) Decreased intake
1-Dietary causes Senility, Alcoholism Hyperalimentation Hemodialysis Prematurity Synthetic diet feeding Goat’s milk feeding
2- Malabsorbtion Nontropical sprue Tropical sprue Intestinal resection Other intestinal diseases
Causes of Folate Causes of Folate DeficiencyDeficiencyB) Increased demands
PregnancyChronic hemolytic diseasesMyeloproliferative diseasesDermatitis(expholiat.)Hyperthyroidism
C) DrugsOral contraseptive drugsSome anticonvulsant drugsTriamtereneCholestyramine
Other causes of megaloblastic Other causes of megaloblastic anemia (1)anemia (1)
I- Combined deficiency of Folate and Vit BI- Combined deficiency of Folate and Vit B12 12 :: Tropical sprueTropical sprue Gluten enteropathyGluten enteropathy
II- Acute megaloblastic anemia:II- Acute megaloblastic anemia: Nitrous oxide anesthesiaNitrous oxide anesthesia Dialysis Dialysis Severe disease + antifolate drug (eg:trimethoprim) Severe disease + antifolate drug (eg:trimethoprim) Total parenteral feedingTotal parenteral feeding
III- Megaloblastic anemia due to drugsIII- Megaloblastic anemia due to drugs Dihydrofolate reductase inhibitors Dihydrofolate reductase inhibitors (eg:MTX,trimethoprim)(eg:MTX,trimethoprim)
Purine antagonists Purine antagonists (eg: 6 MP, azathioprin)(eg: 6 MP, azathioprin)
Pyrimidine antagonists Pyrimidine antagonists ( eg: ARA-C)( eg: ARA-C)
Alkylators Alkylators (eg: cyclophosphamide )(eg: cyclophosphamide )
ZidovudineZidovudine
Other causes of megaloblastic anemia (2)Other causes of megaloblastic anemia (2)
IV- Inherited metabolic diseases:IV- Inherited metabolic diseases: Orotic asiduriaOrotic asiduria Lesch-Nyhan syndromeLesch-Nyhan syndrome Thiamine responsive megaloblastic anemiaThiamine responsive megaloblastic anemia Transcobalamin II deficiencyTranscobalamin II deficiency Homocystinuria , methyl malonic asiduriaHomocystinuria , methyl malonic asiduria Deficiency of enzymes of folate metabolismDeficiency of enzymes of folate metabolism
Methyl tetrahydrofolate transferaseMethyl tetrahydrofolate transferaseFormimino transferaseFormimino transferaseDihydrofolate reductaseDihydrofolate reductase
V- Other: V- Other: Erythroleukemia (?)-not an anemia- alike only Erythroleukemia (?)-not an anemia- alike only
morphologicallymorphologically
Other causes of megaloblastic anemia Other causes of megaloblastic anemia (3)(3)
Clinical features of megaloblastic Clinical features of megaloblastic anemiaanemia
Anemia Atrophic glossitis Neurologic changes
Folic acid deficiency
Vit B12 Deficiency
Tissues or organs other than Tissues or organs other than bone marrow are also affectedbone marrow are also affected
Skin,GIS, female genital system mucosal Skin,GIS, female genital system mucosal epitheliumepithelium
Congenital abn.(neural tube defects)Congenital abn.(neural tube defects) Neurologic changesNeurologic changes(Vit.B(Vit.B1212 deficiency) deficiency)
– Peripheral neuropathyPeripheral neuropathy– Subacute combined degeneration of spinal cordSubacute combined degeneration of spinal cord– Cerebral -Mental changesCerebral -Mental changes
HyperhomocysteinemiaHyperhomocysteinemia
Clinical findings(1)Clinical findings(1) Anemia:Anemia:
Symptoms of anemia + palor+slight icterusSymptoms of anemia + palor+slight icterus
Glossitis :Glossitis :
Sore tongue, poor taste sensation, painSore tongue, poor taste sensation, pain
Papill. atrophy-beefy tonguePapill. atrophy-beefy tongue
Clinical findings(2)Clinical findings(2) Neurologic changes-Vit B12 deficiencyNeurologic changes-Vit B12 deficiency((may occur without anemia)may occur without anemia)
ParesthesiasParesthesiasLoss of position sense, ataxiaLoss of position sense, ataxiaDecreased deep tendon reflexesDecreased deep tendon reflexesMuscle weaknessMuscle weaknessLoss of vibration sense ( post column )Loss of vibration sense ( post column )Spasticity, reflex changes, BabinskySpasticity, reflex changes, Babinsky
(lateral column )(lateral column )RombergRombergMental changes:Memory lossMental changes:Memory loss, confusion, dementia, , confusion, dementia,
hallutination etchallutination etc
Clinical findings(3)Clinical findings(3) Other signs:Other signs:
VitiligoVitiligoHyperpigmentationHyperpigmentationPremature graying of hairPremature graying of hairWeight lossWeight lossFeverFeverDiarheaDiarheaConstipationConstipationMeteorismusMeteorismusSplenomegalySplenomegaly
Peripheral bloodPeripheral blood
CBCCBC::
Anemia Anemia Leukopenia Leukopenia Thrombocytopenia Thrombocytopenia
RBC Indexes:RBC Indexes:
MCVMCV MCHMCH RDWRDW
Peripheral smear(1) :Peripheral smear(1) :
RBC’s RBC’s
Macroovalocytosis ,Macroovalocytosis , Anisocytosis, poikilocytosis , Anisocytosis, poikilocytosis , Bazophilic stippling ,Bazophilic stippling , Howell-Jolly bodies and Cabot ring, Howell-Jolly bodies and Cabot ring, Nucleated red cells Nucleated red cells
Peripheral smear(2) :Peripheral smear(2) :
NeutrophylsNeutrophyls
Neutrophyl hypersegmentation Neutrophyl hypersegmentation
(an early sign of megaloblastic hematopoiesis)(an early sign of megaloblastic hematopoiesis)
Bone marrow findings Bone marrow findings in megaloblastic in megaloblastic anemiaanemia
Bone marrowBone marrow
Hypercellular with erythroid hyperplasia.Hypercellular with erythroid hyperplasia.
Erythroid seriesErythroid series Giant erythroblasts called megaloblastsGiant erythroblasts called megaloblasts Increased numbers of early erythroblastsIncreased numbers of early erythroblasts Nuclear cytoplasmic asynchronismNuclear cytoplasmic asynchronism Increased mytosisIncreased mytosis
Bone marrowBone marrow
Giant metamyelocytes and bandsGiant metamyelocytes and bands
Giant megakaryocytesGiant megakaryocytes
Increased bone marrow iron storesIncreased bone marrow iron stores
Biochemical findingsBiochemical findings
LDHLDH ( LDH -1> LDH - 2)( LDH -1> LDH - 2) Bilirubin(indirect) Bilirubin(indirect) Ferritin and serum iron Ferritin and serum iron Haptoglobin Haptoglobin
Special Lab tests Special Lab tests
1- Vit1- VitBB1212deficiencydeficiency Serum Vit BSerum Vit B1212 Methylmalonic acid Methylmalonic acid
excretion***excretion*** Formiminoglutamate Formiminoglutamate
(FIGlu) excr.(50% cases )(FIGlu) excr.(50% cases ) Radioactive VitBRadioactive VitB12 12
absorbtipon test Deoxyuridine supression Deoxyuridine supression
testtest HyperhomocysteinemiaHyperhomocysteinemia
2-Folate deficiency2-Folate deficiency Serum folateSerum folate(misleads in case of recent folate intake) RBC folate RBC folate (Misleads in cases of Vit B12 deficiency) Formiminoglutamate (FIGlu) Formiminoglutamate (FIGlu)
excretionexcretion Deoxyuridine supression testDeoxyuridine supression test HyperhomocysteinemiaHyperhomocysteinemia
TreatmentTreatment Treat underlying diseaseTreat underlying disease Replacement treatmentReplacement treatment
1- Vit 1- Vit BB1212 deficiency deficiency
cobalamine replacement cobalamine replacement
For 2 weeks: 1000 For 2 weeks: 1000 g / day İMg / day İM
Followed by: Followed by:
1000 1000 g / week until Hb returns to normalg / week until Hb returns to normal
1000 1000 g /mo:life long if g /mo:life long if necessary(eg:pern.anemia)necessary(eg:pern.anemia)
Do not administer folic acid alone to patients with B12 deficiency.Do not administer folic acid alone to patients with B12 deficiency.
Cobalamine replacementCobalamine replacement
Neurologic response is unpredictableNeurologic response is unpredictable BMBM: Megaloblastic changes are lost in 1 - 3 : Megaloblastic changes are lost in 1 - 3
days.days. Reticulocytosis :Reticulocytosis : max:5 – 8 days max:5 – 8 days Hypesegmentation:Hypesegmentation: lost in 1-2 weeks. lost in 1-2 weeks. HbHb:Normalises in 5 – 6 weeks.:Normalises in 5 – 6 weeks. MCV MCV :Normalises in 10 weeks. :Normalises in 10 weeks. Hypokalemia.Hypokalemia.
TreatmentTreatment
2- Folate deficiency2- Folate deficiency Treat underlying conditionTreat underlying condition Folic acid replacement:Folic acid replacement:
Dose :Dose : Start with 1 mg / day ( 2 - 3 weeks )Start with 1 mg / day ( 2 - 3 weeks ) Continue with 0.25 - 0.50 mg / day Continue with 0.25 - 0.50 mg / day Pregnants: 1 mg / dayPregnants: 1 mg / day
Pernicious AnemiaPernicious Anemia
( Addison - Biermer )( Addison - Biermer )
Deficiency of intrinsic factor and Deficiency of intrinsic factor and Megaloblastic anemiaMegaloblastic anemia Athrophic glossitisAthrophic glossitis Neurologic changesNeurologic changes
Types of PA:Types of PA:
Adult: Med: 60 yearsAdult: Med: 60 years Juvenile : 10 - 20 yearsJuvenile : 10 - 20 years Congenital : < 2 yearsCongenital : < 2 years
P.A.P.A.Pathogenesis:
Adult type
Atrophic gastritis:
•Gastric (body)Corpus involved
•All gastric secretions are decresed
•Chief cells and parietal cells are lost and
•intestinal metaplasia may occur.
Congenital type
Selective IF deficiency ( Autosomal res )
Pathogenesis of Gastritis in P.A.Pathogenesis of Gastritis in P.A. Heredity:Heredity:
P.A can be found in the relatives of the patients.P.A can be found in the relatives of the patients. Related to certain HLA antigens ;Related to certain HLA antigens ;
HLA-B7, DW2, DW5, DR2 HLA-B7, DW2, DW5, DR2 Autoimmunity:Autoimmunity: Anti –parietal cell antibodies : 85 %Anti –parietal cell antibodies : 85 % Anti-IF antibodiesAnti-IF antibodies : 55 - 70 % : 55 - 70 % Anti-thyroid antibodiesAnti-thyroid antibodies Other autoimmune diseases and cellular immunityOther autoimmune diseases and cellular immunity
P.A.P.A.
LabLabIn addition to typical blood findings of In addition to typical blood findings of
megaloblastic anemia;megaloblastic anemia; Serum anti-IF antbd***Serum anti-IF antbd*** Serum anti-PC antbdSerum anti-PC antbd Achilia , serum gastrin level increaseAchilia , serum gastrin level increase Gastroscopy and biopsy: atrophic gastitis***Gastroscopy and biopsy: atrophic gastitis*** Schilling’s testSchilling’s test
P.A.P.A.
TreatmentTreatment Life longLife long Cobalamine replacement.Cobalamine replacement.ComplicationComplication Gastric Ca: 2 times normal population Gastric Ca: 2 times normal population